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We have shown previously when R1 is a cycloalkyl
group, that the R enantiomer is favoured.4 For example,
when R1 is cyclopentyl and R2 is 2-methyl-2-pentenyl,
(2R)-8m has a higher M3 receptor affinity than the race-
mate. This trend is followed in the current (1a,5a,6a)-6
amino-3-azabicyclo[3.1.0]hexane series: the 2R isomer of
the benzodioxol 8i has not only a higher M3 receptor
affinity but also a higher M3/M2 receptor selectivity than
the racemate.
References and notes
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In conclusion, we have discovered a novel class of com-
pounds with high affinity for the M3 receptor and high
selectivity over the M2 receptor. Whilst we have
described the SAR of compounds in which the R1 group
is cyclopentyl, compounds having improved in vitro
profiles might be produced when the R1 group is the
more bulky cycloheptyl. In addition, highly potent
antagonists might result from the separation of the
compounds into their homochiral forms and such com-
pounds might be developed as selective M3 muscarinic
receptor antagonists for the treatment of OAB.
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Acknowledgment
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We thank Dr. Kona Srinivas and his Analytical Chem-
istry group for providing analytical support.
10. The affinity of test compounds for the M2 and M3
muscarinic receptor subtypes was determined by [3H]-N-
methylscopolamine binding studies using rat heart and
submandibular gland, respectively, as previously described
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